Whole-Genome Doubling as a source of cancer: how, when, where, and why?

Abstract

Chromosome instability is a well-known hallmark of cancer, leading to increased genetic plasticity of tumoral cells, which favors cancer aggressiveness, and poor prognosis. One of the main sources of chromosomal instability are events that lead to a Whole-Genome Duplication (WGD) and the subsequently generated cell polyploidy. In recent years, several studies showed that WGD occurs at the early stages of cell transformation, which allows cells to later become aneuploid, thus leading to cancer progression. On the other hand, other studies convey that polyploidy plays a tumor suppressor role, by inducing cell cycle arrest, cell senescence, apoptosis, and even prompting cell differentiation, depending on the tissue cell type. There is still a gap in understanding how cells that underwent WGD can overcome the deleterious effect on cell fitness and evolve to become tumoral. Some laboratories in the chromosomal instability field recently explored this paradox, finding biomarkers that modulate polyploid cells to become oncogenic. This review brings a historical view of how WGD and polyploidy impact cell fitness and cancer progression, and bring together the last studies that describe the genes helping cells to adapt to polyploidy.

Keywords: aneuploidy; chromosomal instability; endoreduplication; mitotic slippage; oncogene; polyploidy; whole-genome doubling.

FIGURE 1

Whole-Genome Doubling: How, and Where. WGD has been described in multiple cell types such as trophoblasts, megakaryocytes, cardiomyocytes, or hepatocytes. The molecular mechanisms leading to WGD are multiple and mainly differ in the specific cell cycle phase from which they arise. Endoreduplication occurs when cells skip entry into mitosis from G2. Mitotic slippage or endomitosis occurs when the cell arrests in mitosis due to activation of the mitotic spindle assembly checkpoint (SAC) and eventually slip mitosis without segregating the genetic material. Cytokinesis failure occurs when cells are unable to properly form the contractile ring at the mitotic midbody and fail to divide. Each event is triggered by different molecular stimuli (examples in orange) and is specific for different cell types and tissues (purple squares). Cartoons were generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

FIGURE 2

The effect of WGD on tumor prognosis is cancer-type dependent. Different tumor cohorts were examined to show examples of cancer types where WGD provides poor prognosis (A–C) (BRCA, Breast invasive Carcinoma; KIRC, Kidney renal clear cell carcinoma; UCEC, Uterine Corpus Endometrial Carcinoma); or favorable prognosis (D) (BLCA, Bladder Urothelial Carcinoma), as shown by disease-free specific survival (DSS) in Kaplan-Meier analysis. Data from primary tumor samples were extracted from the TCGA Pan-Cancer Atlas (Weinstein et al., 2013). Ploidy values were obtained from the ABSOLUTE mastercalls file (Carter et al., 2012). WGD groups (WGD- and WGD+) were calculated with the ploidy value and a membership probability estimated by bootstrap (ASURI, R package under preparation (Bueno-Fortes et al., 2023)). Samples with a membership probability greater than 0.8 were considered for the analysis. Kaplan–Meier plots with a fitted Cox model (Therneau, 2023) for the two groups were represented with the Disease Specific Survival (DSS) information of each patient.

FIGURE 3

WGD as a source of aneuploidy and CIN: Diploid cells (2N—where ‘N' denotes the number of chromosomes) can slip cell division, during the S/G2 or mitosis phases, leading to a WGD event and a tetraploid state (4N). Tetraploid cells arrest in the next G1 phase due to the activation of a tetraploid checkpoint eventually triggering a non-proliferative state (senescence, terminal differentiation). When 4N cells re-enter the second cell cycle and replicate the DNA (8N), will be exposed to replication stress and chromosome missegregation alterations (DNA damage by red stars, centrosomes by black ovals). Adaptation to these alterations will generate aneuploidy (4N + n, 4N-n, where “n” refers to the number of missegregated chromosomes) and further chromosomal instability (CIN). The Figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

FIGURE 4

Genetic determinants balancing WGD towards oncogene or tumor suppressor fate. HIPPO signaling, cell cycle genes like PLK1, or DNA damage-related genes such as TP53, USP28, or SPINT2 play as tumor suppressors in a WGD context. On the other hand, increased YAP transcription activity, and overexpression of Cyclin E, Aurora kinase A (AurKA), GINS1, CDC45 or KIF18A leads to oncogenic progression in WGD cells.